Project Summary Salt-sensitivity of blood pressure (BP) is associated with increased risk of hypertension and cardiovascular disease mortality. The underlying mechanism of salt-sensitivity is not fully understood. The overall objective of the proposed study is to investigate the association of urinary excretion of angiotensinogen (AGT), kallikrein, dopamine, norepinephrine, and albumin with salt-sensitivity and potassium-sensitivity of BP and risk of hypertension. The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) is an NHLBI-sponsored dietary feeding-study conducted among 1,906 participants living in rural China during October 2003-July 2005. The dietary interventions included a 7-day low-sodium feeding (51.3 mmol/day), a 7-day high-sodium feeding (307.8 mmol/day), and a 7-day high-sodium feeding with oral potassium supplementation (60 mmol/day). BP measurements were obtained on each of 3 days during the baseline and each of the 3 intervention periods. Two follow-up examinations to investigate the incidence of hypertension were conducted in the GenSalt study participants during August 2008-December 2009 and August 2011-May 2012. The GenSalt-replication study was conducted among 698 participants living in the same region using an identical study protocol from April to November of 2010. The GenSalt and GenSalt-replication studies with high quality data and sufficient biosamples provide a unique opportunity for the following specific aims: 1. to investigate the association of urinary excretion of AGT, kallikrein, dopamine, norepinephrine, and albumin with salt- and potassium- sensitivity of BP, and 2. to study the prospective association of urinary excretion of AGT, kallikrein, dopamine, norepinephrine, and albumin with subsequent incidence of hypertension. To achieve these specific aims, we will measure urinary AGT, kallikrein, dopamine, norepinephrine, and albumin in the frozen-stored 24-hour urinary samples from the GenSalt and GenSalt-replication study participants; analyze the association of urinary excretion of biomarkers at baseline and during dietary interventions with BP responses to dietary sodium and potassium interventions in 2,604 GenSalt and GenSalt-replication study participants; and analyze the prospective relationship of urinary excretion of biomarkers at baseline and during dietary interventions with subsequent risk of hypertension in 1,906 GenSalt study participants with follow-up data on BP. The proposed study is very timely and cost-effective, because it uses the rich resources and research infrastructure of the GenSalt study. This study will be the first large investigation to examine the association between multiple urinary biomarkers and risk of salt-sensitive hypertension. The findings from this study may provide novel insights into the underlying biologic mechanisms of salt-sensitivity and potassium-sensitivity of BP. The study findings may also help to identify novel biomarkers for salt-sensitivity and potassium-sensitivity of BP and for the prediction of hypertension risk. Finally, the findings from this study may help to develop new pharmaceutical treatments for salt-sensitive hypertension.